|
Inhibitory concentration towards in human monoamine oxidase A was measured
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Inactivation of purified human recombinant monoamine oxidases A and B by rasagiline and its analogues.
Year : 2004
Volume : 47
Issue : 7
First Page : 1760
Last Page : 1766
Authors : Hubálek F, Binda C, Li M, Herzig Y, Sterling J, Youdim MB, Mattevi A, Edmondson DE.
Abstract : The inactivation of purified human recombinant monoamine oxidases (MAO) A and B by rasagiline [N-propargyl-1(R)-aminoindan] and four of its analogues [N-propargyl-1(S)-aminoindan (S-PAI), 6-hydroxy-N-propargyl-1(R)-aminoindan (R-HPAI), N-methyl-N-propargyl-1(R)-aminoindan (R-MPAI), and 6-(N-methyl-N-ethyl carbamoyloxy)-N-propargyl-1(R)-aminoindan (R-CPAI)] has been investigated. All compounds tested, with the exception of R-CPAI, form stoichiometric N(5) flavocyanine adducts with the FAD moiety of either enzyme. No H(2)O(2) is produced during either MAO A or MAO B inactivation, which demonstrates that covalent addition occurs in a single turnover. Rasagiline has the highest specificity for MAO B, as demonstrated by a 100-fold higher inhibition potency (k(inact)/K(i)) compared to MAO A, with the remaining compounds exhibiting lower isozyme specificities. MAO B and MAO A are more selective for the R-enantiomer (rasagiline) compared to the S-enantiomer (S-PAI) by 2500-fold and 17-fold, respectively. Differences in UV/vis and CD spectral data of the complexes of the studied compounds with both MAO A and MAO B are interpreted in light of crystallographic data of complexes of MAO B with rasagiline and its analogues (Binda, C.; et al. J. Med. Chem. 2004, 47, 1767-1774.
|
In vitro inhibitory concentration against Monoamine oxidase A of rat brain homogenates; value ranges from 0.28-0.54
|
None
|
410.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease.
Year : 2002
Volume : 45
Issue : 24
First Page : 5260
Last Page : 5279
Authors : Sterling J, Herzig Y, Goren T, Finkelstein N, Lerner D, Goldenberg W, Miskolczi I, Molnar S, Rantal F, Tamas T, Toth G, Zagyva A, Zekany A, Finberg J, Lavian G, Gross A, Friedman R, Razin M, Huang W, Krais B, Chorev M, Youdim MB, Weinstock M.
Abstract : Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere.
|
Inhibitory concentration towards in human monoamine oxidase B was measured
|
None
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Inactivation of purified human recombinant monoamine oxidases A and B by rasagiline and its analogues.
Year : 2004
Volume : 47
Issue : 7
First Page : 1760
Last Page : 1766
Authors : Hubálek F, Binda C, Li M, Herzig Y, Sterling J, Youdim MB, Mattevi A, Edmondson DE.
Abstract : The inactivation of purified human recombinant monoamine oxidases (MAO) A and B by rasagiline [N-propargyl-1(R)-aminoindan] and four of its analogues [N-propargyl-1(S)-aminoindan (S-PAI), 6-hydroxy-N-propargyl-1(R)-aminoindan (R-HPAI), N-methyl-N-propargyl-1(R)-aminoindan (R-MPAI), and 6-(N-methyl-N-ethyl carbamoyloxy)-N-propargyl-1(R)-aminoindan (R-CPAI)] has been investigated. All compounds tested, with the exception of R-CPAI, form stoichiometric N(5) flavocyanine adducts with the FAD moiety of either enzyme. No H(2)O(2) is produced during either MAO A or MAO B inactivation, which demonstrates that covalent addition occurs in a single turnover. Rasagiline has the highest specificity for MAO B, as demonstrated by a 100-fold higher inhibition potency (k(inact)/K(i)) compared to MAO A, with the remaining compounds exhibiting lower isozyme specificities. MAO B and MAO A are more selective for the R-enantiomer (rasagiline) compared to the S-enantiomer (S-PAI) by 2500-fold and 17-fold, respectively. Differences in UV/vis and CD spectral data of the complexes of the studied compounds with both MAO A and MAO B are interpreted in light of crystallographic data of complexes of MAO B with rasagiline and its analogues (Binda, C.; et al. J. Med. Chem. 2004, 47, 1767-1774.
|
Binding affinity towards monoamine oxidase B activity was measured using a benzylamine assay
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Inactivation of purified human recombinant monoamine oxidases A and B by rasagiline and its analogues.
Year : 2004
Volume : 47
Issue : 7
First Page : 1760
Last Page : 1766
Authors : Hubálek F, Binda C, Li M, Herzig Y, Sterling J, Youdim MB, Mattevi A, Edmondson DE.
Abstract : The inactivation of purified human recombinant monoamine oxidases (MAO) A and B by rasagiline [N-propargyl-1(R)-aminoindan] and four of its analogues [N-propargyl-1(S)-aminoindan (S-PAI), 6-hydroxy-N-propargyl-1(R)-aminoindan (R-HPAI), N-methyl-N-propargyl-1(R)-aminoindan (R-MPAI), and 6-(N-methyl-N-ethyl carbamoyloxy)-N-propargyl-1(R)-aminoindan (R-CPAI)] has been investigated. All compounds tested, with the exception of R-CPAI, form stoichiometric N(5) flavocyanine adducts with the FAD moiety of either enzyme. No H(2)O(2) is produced during either MAO A or MAO B inactivation, which demonstrates that covalent addition occurs in a single turnover. Rasagiline has the highest specificity for MAO B, as demonstrated by a 100-fold higher inhibition potency (k(inact)/K(i)) compared to MAO A, with the remaining compounds exhibiting lower isozyme specificities. MAO B and MAO A are more selective for the R-enantiomer (rasagiline) compared to the S-enantiomer (S-PAI) by 2500-fold and 17-fold, respectively. Differences in UV/vis and CD spectral data of the complexes of the studied compounds with both MAO A and MAO B are interpreted in light of crystallographic data of complexes of MAO B with rasagiline and its analogues (Binda, C.; et al. J. Med. Chem. 2004, 47, 1767-1774.
|
In vitro inhibitory concentration against Monoamine oxidase B of rat brain homogenates; value ranges from 0.0035-0.053
|
None
|
4.4
nM
|
|
Journal : J. Med. Chem.
Title : Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease.
Year : 2002
Volume : 45
Issue : 24
First Page : 5260
Last Page : 5279
Authors : Sterling J, Herzig Y, Goren T, Finkelstein N, Lerner D, Goldenberg W, Miskolczi I, Molnar S, Rantal F, Tamas T, Toth G, Zagyva A, Zekany A, Finberg J, Lavian G, Gross A, Friedman R, Razin M, Huang W, Krais B, Chorev M, Youdim MB, Weinstock M.
Abstract : Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme. Compounds with such dual AChE and MAO inhibitory activities are expected to have potential for the treatment of Alzheimer's disease. The observed SAR also offers insight into the requirements of the active sites on these enzymes. A carbamate moiety was found to be essential for AChE inhibition, which was absent in the corresponding hydroxy precursors. The propargyl group caused 2-70-fold decrease in AChE inhibitory activity (depending on the position of the carbamoyl group) of Series I, but had little or no effect in Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were either equipotent to, or slightly (2- to 5-fold) less active as AChE inhibitors than, the corresponding compounds in Series II, while the 4-carbamyloxyphenyls were more potent. The presence of the carbamate moiety in 6- and 7-carbamyloxyphenyls of Series I, considerably decreased MAO-A and -B inhibitory activity, compared to that of the parent hydroxy analogues, while the opposite was true for Series II. Thus, the 6- and 7-carbamyloxyphenyls in Series I were 2-3 orders of magnitude weaker MAO inhibitors while the 4- carbamyloxyphenyls were equipotent with the corresponding compounds in Series II. In both series, N-methylation of the propargylamine enhanced the MAO (A and B equally) inhibitory activities and decreased the AChE inhibitory activity. Two candidates belonging to the indan and tetralin ring systems (24c, 27b) and one phenethylamine (53d) were identified as possible leads for further development based on the following criteria: (a) comparable AChE and MAO-B inhibitory activities, (b) good to moderate AChE inhibitory activity, and (c) lack of strong MAO-A selectivity. However, it is likely that these compounds will be metabolized to the corresponding phenols, with inhibitory activities against AChE and/or MAO-A or -B, different from those of the parent carbamates. Thus, the apparent enzyme inhibition will be a result of the combined inhibition of all of these individual metabolites. The results of our ongoing in vivo screening programs will be published elsewhere.
|
Inhibition constant against human recombinant Monoamine oxidase-B
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Docking studies on monoamine oxidase-B inhibitors: estimation of inhibition constants (K(i)) of a series of experimentally tested compounds.
Year : 2005
Volume : 15
Issue : 20
First Page : 4438
Last Page : 4446
Authors : Toprakçí M, Yelekçi K.
Abstract : Monoamine oxidase (EC1.4.3.4; MAO) is a mitochondrial outer membrane flavoenzyme that catalyzes the oxidation of biogenic amines. It has two distinct isozymic forms designated MAO-A and MAO-B, each displaying different substrate and inhibitor specificities. They are the well-known targets for antidepressant and neuroprotective drugs. Elucidation of the X-ray crystallographic structure of MAO-B has opened the way for molecular modeling studies. A series of experimentally tested (1-10) model compounds has been docked computationally to the active site of the MAO-B enzyme. The AutoDock 3.0.5 program was employed to perform automated molecular docking. The free energies of binding (DeltaG) and inhibition constants (K(i)) of the docked compounds were calculated by the Lamarckian Genetic Algorithm (LGA) of AutoDock 3.0.5. Excellent to good correlations between the calculated and experimental K(i) values were obtained.
|
Inhibition of MAOA
|
None
|
410.0
nM
|
|
Journal : J. Med. Chem.
Title : Multi-target-directed ligands to combat neurodegenerative diseases.
Year : 2008
Volume : 51
Issue : 3
First Page : 347
Last Page : 372
Authors : Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C.
|
Inhibition of MAOB
|
None
|
4.4
nM
|
|
Journal : J. Med. Chem.
Title : Multi-target-directed ligands to combat neurodegenerative diseases.
Year : 2008
Volume : 51
Issue : 3
First Page : 347
Last Page : 372
Authors : Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C.
|
Inhibition of human recombinant MAO-B expressed in insect cells assessed as kynuramine hydrobromide oxidation after 20 mins by spectrophotometric analysis
|
Homo sapiens
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of [¹⁸F]fluororasagiline, a novel positron emission tomography (PET) radioligand for monoamine oxidase B (MAO-B).
Year : 2012
Volume : 20
Issue : 9
First Page : 3065
Last Page : 3071
Authors : Nag S, Lehmann L, Kettschau G, Heinrich T, Thiele A, Varrone A, Gulyas B, Halldin C.
Abstract : The aim of this study was to synthesize and evaluate a novel fluorine-18 labeled analogue of rasagiline (6) as a PET radioligand for monoamine oxidase B (MAO-B). The corresponding non-radioactive fluorine-19 ligand, (1S,2S)-2-fluoro-N-(prop-2-yn-1-yl)indan-1-amine (4), was characterized in in vitro assays. The precursor compound (3aS,8aR)-3-(prop-2-yn-1-yl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole 2,2-dioxide (3) and reference standard 4 were synthesized in multi-step syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used in order to determine IC(50) values for compound 4 by use of an enzymatic assay employing kynuramine as substrate. Radiolabeling was accomplished by a two-step synthesis, compromising a nucleophilic substitution followed by hydrolysis of the sulphamidate group. Human whole hemisphere autoradiography (ARG) was performed with [(18)F]fluororasagiline. Blocking experiments with pirlindole (MAO-A), L-deprenyl and rasagiline (MAO-B) were conducted to demonstrate the specificity of the binding. A positron emission tomography (PET) study was carried out in a cynomolgus monkey where time activity curves for whole brain and regions with high and low MAO-B activity were recorded. Radiometabolites were measured in monkey plasma using gradient HPLC. Compound 4 inhibited MAO-B with an IC(50) of 27 nM and MAO-A with an IC(50) of 2.3 μM. Radiolabeling of precursor 3 and subsequent hydrolysis of the protecting group towards (1S,2S)-2-[(18)F]fluoro-N-(prop-2-yn-1-yl)indan-1-amine (6) was successfully accomplished with an radiochemical yield of 40-70%, a radiochemical purity higher than 99% and a specific radioactivity higher than 200GBq/μmol. ARG demonstrated selective binding for [(18)F]fluororasagiline (6) to MAO-B containing brain regions, for example, striatum. The initial uptake in the monkey brain was 250% SUV at 4 min post injection. The highest amounts of radioactivity were observed in the striatum and thalamus as expected whereas in the cortex and cerebellum lower levels were observed. Metabolite studies demonstrated 30% unchanged radioligand at 90 min post injection. Our investigations demonstrated that the new ligand [(18)F]fluororasagiline (6) binds specifically to MAO-B in vitro and has a MAO-B specific binding pattern in vivo. Thus, it could serve as a novel potential candidate for human PET studies.
|
Inhibition of human recombinant MAOA assessed as H2O2 production by Amplex Red reagent-based assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Multitarget-directed benzylideneindanone derivatives: anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer's disease.
Year : 2012
Volume : 55
Issue : 19
First Page : 8483
Last Page : 8492
Authors : Huang L, Lu C, Sun Y, Mao F, Luo Z, Su T, Jiang H, Shan W, Li X.
Abstract : A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ(1-42)) aggregation (10.5-80.1%, 20 μM) and MAO-B activity (IC(50) of 7.5-40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75-9.37), and to function as metal chelators. In particular, compound 41 had the greatest ability to inhibit Aβ(1-42) aggregation (80.1%), and MAO-B (IC(50) = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu(II)-induced Aβ(1-42) aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound 41 is an excellent multifunctional agent for the treatment of AD.
|
Inhibition of human recombinant MAOB assessed as H2O2 production by Amplex Red reagent-based assay
|
Homo sapiens
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Multitarget-directed benzylideneindanone derivatives: anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer's disease.
Year : 2012
Volume : 55
Issue : 19
First Page : 8483
Last Page : 8492
Authors : Huang L, Lu C, Sun Y, Mao F, Luo Z, Su T, Jiang H, Shan W, Li X.
Abstract : A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ(1-42)) aggregation (10.5-80.1%, 20 μM) and MAO-B activity (IC(50) of 7.5-40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75-9.37), and to function as metal chelators. In particular, compound 41 had the greatest ability to inhibit Aβ(1-42) aggregation (80.1%), and MAO-B (IC(50) = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu(II)-induced Aβ(1-42) aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound 41 is an excellent multifunctional agent for the treatment of AD.
|
Inhibition of human recombinant microsomal MAO-B expressed in baculovirus infected BTI-TN-5B1-4 cells using p-tyramine as substrate assessed as production of H2O2 incubated for 15 mins followed by substrate addition measured over 15 mins by fluorimetric analysis
|
Homo sapiens
|
69.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Novel (coumarin-3-yl)carbamates as selective MAO-B inhibitors: synthesis, in vitro and in vivo assays, theoretical evaluation of ADME properties and docking study.
Year : 2013
Volume : 63
First Page : 151
Last Page : 161
Authors : Matos MJ, Vilar S, Gonzalez-Franco RM, Uriarte E, Santana L, Friedman C, Tatonetti NP, Viña D, Fontenla JA.
Abstract : A series of (coumarin-3-yl)carbamates was synthesized and evaluated in vitro as monoamine oxidase (MAO-A and MAO-B) inhibitors. Most of the new compounds selectively inhibited MAO-B isoenzyme with IC50 values in the micro or nanoMolar ranges. Since these compounds must achieve the brain cells, theoretical evaluation of ADME properties were also carried out. Compound 8 (benzyl(coumarin-3-yl)carbamate), which presented the most interesting in vitro MAO-B inhibitory profile (IC50 against MAO-B = 45 nM), was subjected to further studies. This in vitro MAO-B inhibitory activity is comparable with that of the selegiline, the reference compound (IC50 against MAO-B = 20 nM). Taking into account the in vitro results of compound 8, in vivo assays and docking calculations were also carried out for this derivative.
|
Inhibition of recombinant human MAO-B expressed in insect cells using kynuramine as substrate assessed as formation of 4-hydroxyquinoline measured every 5 mins for 30 mins
|
Homo sapiens
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Development of a novel fluorine-18 labeled deuterated fluororasagiline ([(18)F]fluororasagiline-D2) radioligand for PET studies of monoamino oxidase B (MAO-B).
Year : 2013
Volume : 21
Issue : 21
First Page : 6634
Last Page : 6641
Authors : Nag S, Lehmann L, Kettschau G, Toth M, Heinrich T, Thiele A, Varrone A, Halldin C.
Abstract : The objective of this study was to synthesize and evaluate a novel fluorine-18 labeled deuterium substituted analogue of rasagiline (9, [(18)F]fluororasagiline-D2) as a potential PET radioligand for studies of monoamine oxidase B (MAO-B). The precursor compound (6) and reference standard (7) were synthesized in multi-step syntheses. Radiolabeling of 9 was accomplished by a two-step synthesis, compromising a nucleophilic substitution followed by hydrolysis of the sulfamidate group. The incorporation radiochemical yield from fluorine-18 fluoride was higher than 30%, the radiochemical purity was >99% and the specific radioactivity was >160GBq/μmol at the time of administration. In vitro compound 7 inhibited the MAO-B activity with an IC50 of 173.0±13.6nM. The MAO-A activity was inhibited with an IC50 of 9.9±1.1μM. The fluorine-18 version 9 was characterized in the cynomolgus monkey brain where a high brain uptake was found (275% SUV at 4min). There was a higher uptake in the striatum and thalamus compared to the cortex and cerebellum. A pronounced blocking effect (50% decrease) was observed in the specific brain regions after administration of l-deprenyl (0.5mg/kg) 30min prior to the administration of 9. Radiometabolite studies demonstrated 40% of unchanged radioligand at 90min post injection. An efficient radiolabeling of 9 was successfully established and in the monkey brain 9 binds to MAO-B rich regions and its binding is blocked by the selective MAO-B compound l-deprenyl. The radioligand 9 is a potential candidate for human PET studies.
|
Binding affinity to human recombinant MAOB
|
Homo sapiens
|
700.0
nM
|
|
Journal : MedChemComm
Title : Identification of multifunctional small molecule-based reversible monoamine oxidase inhibitors
Year : 2011
Volume : 2
Issue : 11
First Page : 1099
Last Page : 1103
Authors : Geldenhuys WJ, Ko KS, Stinnett H, Van der Schyf CJ, Lim MH
|
Irreversible inhibition of human recombinant MAOB
|
Homo sapiens
|
14.0
nM
|
|
Journal : MedChemComm
Title : Identification of multifunctional small molecule-based reversible monoamine oxidase inhibitors
Year : 2011
Volume : 2
Issue : 11
First Page : 1099
Last Page : 1103
Authors : Geldenhuys WJ, Ko KS, Stinnett H, Van der Schyf CJ, Lim MH
|
Inhibition of human recombinant microsomal MAO-B expressed in Pichia pastoris incubated for 30 mins prior to substrate addition measured after 60 mins by MAO-Glo assay
|
Homo sapiens
|
14.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques.
Year : 2015
Volume : 23
Issue : 4
First Page : 770
Last Page : 778
Authors : Rojas RJ, Edmondson DE, Almos T, Scott R, Massari ME.
Abstract : Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.
|
Inhibition of human recombinant soluble MAO-B expressed in Pichia pastoris incubated for 30 mins prior to substrate addition measured after 60 mins by MAO-Glo assay
|
Homo sapiens
|
7.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques.
Year : 2015
Volume : 23
Issue : 4
First Page : 770
Last Page : 778
Authors : Rojas RJ, Edmondson DE, Almos T, Scott R, Massari ME.
Abstract : Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.
|
Inhibition of rat brain MAO-A in nuclei-free homogenates using [14C]hydroxytryptamine substrate after 20 mins by liquid scintillation counting
|
Rattus norvegicus
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel arylalkenylpropargylamines as neuroprotective, potent, and selective monoamine oxidase B inhibitors for the treatment of Parkinson's disease.
Year : 2015
Volume : 58
Issue : 3
First Page : 1400
Last Page : 1419
Authors : Huleatt PB, Khoo ML, Chua YY, Tan TW, Liew RS, Balogh B, Deme R, Gölöncsér F, Magyar K, Sheela DP, Ho HK, Sperlágh B, Mátyus P, Chai CL.
Abstract : To develop novel neuroprotective agents, a library of novel arylalkenylpropargylamines was synthesized and tested for inhibitory activities against monoamine oxidases. From this, a number of highly potent and selective monoamine oxidase B inhibitors were identified. Selected compounds were also tested for neuroprotection in in vitro studies with PC-12 cells treated with 6-OHDA and rotenone, respectively. It was observed that some of the compounds tested yielded a marked increase in survival in PC-12 cells treated with the neurotoxins. This indicates that these propargylamines are able to confer protection against the effects of the toxins and may also be considered as novel disease-modifying anti-Parkinsonian agents, which are much needed for the therapy of Parkinson's disease.
|
Inhibition Assay: MAO-A and MAO-B activity was measured using radioactive substrates. The substrate for MAO-A was 5 HT and for MAO-B was PEA. When measuring the activity of MAO-A, the MAO-B activity was inhibited with deprenyl and when measuring the activity of MAO-B the activity of MAO-A was inhibited with clorgylin. Blank samples were produced using TCP to inhibit both of the enzymes. The metabolites were extracted to toluene and read in a β -counter. The results are expressed in relative activity and normalized to the amount of protein in the tissue. Figs. 1 and 2 show MAO-A/MAO-B activity of compounds 3, 4 and of 0-Methyl-M3O at various concentrations (10 -"5 -10 -"8 ). As presented in Figs. 1 and 2, it can be seen that compounds 3, 4 and 0-Methyl-M3O were all potent inhibitors of MAO-A and MAO-B extracted from rat brain, compound 3 clearly the most potent inhibitor of the three compounds.
|
Homo sapiens
|
410.0
nM
|
|
Title : Neuroprotective and neuro-restorative iron chelators and monoamine oxidase inhibitors and uses thereof
Year : 2015
|
Inhibition Assay: MAO-A and MAO-B activity was measured using radioactive substrates. The substrate for MAO-A was 5 HT and for MAO-B was PEA. When measuring the activity of MAO-A, the MAO-B activity was inhibited with deprenyl and when measuring the activity of MAO-B the activity of MAO-A was inhibited with clorgylin. Blank samples were produced using TCP to inhibit both of the enzymes. The metabolites were extracted to toluene and read in a β -counter. The results are expressed in relative activity and normalized to the amount of protein in the tissue. Figs. 1 and 2 show MAO-A/MAO-B activity of compounds 3, 4 and of 0-Methyl-M3O at various concentrations (10 -"5 -10 -"8 ). As presented in Figs. 1 and 2, it can be seen that compounds 3, 4 and 0-Methyl-M3O were all potent inhibitors of MAO-A and MAO-B extracted from rat brain, compound 3 clearly the most potent inhibitor of the three compounds.
|
Homo sapiens
|
4.0
nM
|
|
Title : Neuroprotective and neuro-restorative iron chelators and monoamine oxidase inhibitors and uses thereof
Year : 2015
|
Inhibition of human recombinant MAO-B using kynuramine as substrate after 30 mins by fluorescence spectrophotometry
|
Homo sapiens
|
82.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of 4-hydroxyl aurone derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2016
Volume : 24
Issue : 10
First Page : 2342
Last Page : 2351
Authors : Li Y, Qiang X, Luo L, Li Y, Xiao G, Tan Z, Deng Y.
Abstract : A series of 4-hydroxyl aurone derivatives were designed synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The results demonstrated that most of the derivatives exhibited good multifunctional properties. Among them, compound 14e displayed good inhibitory activities of self- and Cu(2+)-induced Aβ1-42 aggregation with 99.2% and 84.0% at 25μM, respectively, and high antioxidant activity with a value 1.90-fold of Trolox. In addition, 14e also showed remarkable inhibitory activities of both monoamine oxidase A and B with IC50 values of 0.271μM and 0.393μM, respectively. However the 6-methoxyl aurones 15a-c revealed excellent selectivity toward MAO-B. Furthermore, the representative compounds 14e and 15b displayed good metal-chelating abilities and blood-brain barrier (BBB) permeabilities in vitro.
|
Inhibition of recombinant human MAO-B using p-tyramine as substrate assessed as decrease in H2O2 production incubated for 15 mins by fluorimetric method
|
Homo sapiens
|
7.87
nM
|
|
Journal : Bioorg Med Chem
Title : Neuroprotective effects of benzyloxy substituted small molecule monoamine oxidase B inhibitors in Parkinson's disease.
Year : 2016
Volume : 24
Issue : 22
First Page : 5929
Last Page : 5940
Authors : Wang Z, Wu J, Yang X, Cai P, Liu Q, Wang KDG, Kong L, Wang X.
Abstract : The benzyloxy substituted small molecules are well-known highly potent monoamine oxidase B inhibitors, but their therapeutic potential against Parkinson's disease have not been investigated in detail. In this paper, a series of representative benzyloxy substituted derivatives were synthesized and evaluated for MAO-A/B inhibition. In addition, their neuroprotective effects were investigated in 6-OHDA- and rotenone-treated PC12 cells. It was observed that most of the compounds exhibited a marked increase in survival of PC12 cells which treated with the neurotoxins. Among them, 13 exhibited remarkable and balanced neuroprotective potency. The protective effects of 13 against neurotoxins-induced apoptosis were confirmed with flow cytometry and staining methods. Furthermore, 13 also showed good BBB permeability and low toxicity according to in vitro BBB prediction and in vivo acute toxicity test. The results indicated that 13 is an effective and promising candidate to be further developed as disease-modifying drug for Parkinson's disease therapy.
|
Inhibition of human recombinant MAO-B using kynuramine as substrate measured after 30 mins by fluorescence assay
|
Homo sapiens
|
82.5
nM
|
|
Journal : Bioorg Med Chem
Title : Multitarget drug design strategy against Alzheimer's disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties.
Year : 2017
Volume : 25
Issue : 2
First Page : 714
Last Page : 726
Authors : Li Y, Qiang X, Luo L, Yang X, Xiao G, Zheng Y, Cao Z, Sang Z, Su F, Deng Y.
Abstract : A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC50=2.49±0.08nM and 1.74±0.0581μM, respectively), good self- and Cu2+-induced Aβ1-42 aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability. These multifunctional properties make 10d as an excellent candidate for the development of efficient drugs against AD.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected High 5 insect cells using kynuramine as substrate incubated for 30 mins by spectrofluorometric method
|
Homo sapiens
|
83.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 4'-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2017
Volume : 25
Issue : 3
First Page : 1030
Last Page : 1041
Authors : Xiao G, Li Y, Qiang X, Xu R, Zheng Y, Cao Z, Luo L, Yang X, Sang Z, Su F, Deng Y.
Abstract : A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC50=4.91μM), and significant antioxidative activity with a value 2.83-fold of Trolox. The kinetic analysis of AChE inhibition revealed that 6c showed mixed-type inhibition, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. In addition, 6c inhibited self-induced Aβ1-42 aggregation and Cu2+-induced Aβ1-42 aggregation by 89.5% and 79.7% at 25μM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50=0.29μM) and a selective biometal chelator. Furthermore, 6c could cross the blood-brain barrier in vitro. Based on these results, Compound 6c could be considered as a very promising lead compound for Alzheimer's disease.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate after 30 mins by fluorimetric method
|
Homo sapiens
|
9.97
nM
|
|
Journal : Bioorg Med Chem
Title : Multifunctional thioxanthone derivatives with acetylcholinesterase, monoamine oxidases and β-amyloid aggregation inhibitory activities as potential agents against Alzheimer's disease.
Year : 2017
Volume : 25
Issue : 6
First Page : 1997
Last Page : 2009
Authors : Luo L, Li Y, Qiang X, Cao Z, Xu R, Yang X, Xiao G, Song Q, Tan Z, Deng Y.
Abstract : A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer's disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self- and Cu2+-induced Aβ1-42 aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC50=0.59±0.02μM), MAO-A and MAO-B (IC50=1.01±0.02μM and 0.90±0.01μM respectively), excellent efficiency to block both self- and Cu2+-induced Aβ1-42 aggregation (74.8±1.2% and 87.7±1.9% at 25μM, respectively), good metal-chelating property and a low toxicity in SH-SY5Y cells. Furthermore, kinetic and molecular modeling studies revealed that compound 9e binds simultaneously to the catalytic active site and peripheral anionic site of AChE, and could penetrate the BBB. Collectively, these results suggested that 9e might be a potential multifunctional agent for further development in the treatment of AD.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate incubated for 30 mins by fluorescence assay
|
Homo sapiens
|
82.5
nM
|
|
Journal : Eur J Med Chem
Title : Aurone Mannich base derivatives as promising multifunctional agents with acetylcholinesterase inhibition, anti-β-amyloid aggragation and neuroprotective properties for the treatment of Alzheimer's disease.
Year : 2017
Volume : 126
First Page : 762
Last Page : 775
Authors : Li Y, Qiang X, Luo L, Yang X, Xiao G, Liu Q, Ai J, Tan Z, Deng Y.
Abstract : A series of aurone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compound 7d exhibited outstanding inhibitory activity for RatAChE, EeAChE and HuAChE (IC50 = 0.00878 ± 0.0002 μM, 0.0212 ± 0.006 μM and 0.0371 ± 0.004 μM, respectively). Moreover, 7d displayed high antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. In addition, 7d also showed biometal chelating abilities, good self- and Cu2+-induced Aβ1-42 aggregation inhibitory potency and high BBB permeability. These multifunctional properties highlight 7d as promising candidate for further studies directed to the development of novel drugs against AD.
|
Inhibition of recombinant human MAO-A using kynuramine as substrate after 30 mins by fluorescence assay
|
Homo sapiens
|
710.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : DL-3-n-butylphthalide-Edaravone hybrids as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases with high antioxidant potency for Alzheimer's therapy.
Year : 2017
Volume : 27
Issue : 4
First Page : 718
Last Page : 722
Authors : Qiang X, Li Y, Yang X, Luo L, Xu R, Zheng Y, Cao Z, Tan Z, Deng Y.
Abstract : Considering the complex etiology of Alzheimer's disease (AD), multifunctional agents may be beneficial for the treatment of this disease. A series of DL-3-n-butylphthalide-Edaravone hybrids were designed, synthesized and evaluated as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases. Among them, compounds 9a-d exhibited good inhibition of self-induced Aβ1-42 aggregation with inhibition ratio 57.7-71.5%. For MAO, these new hybrids exhibited good balance of inhibition for MAO-A and MAO-B. In addition, all target compounds retained the antioxidant activity of edaravone, showed equal or better antioxidant activity than edaravone. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compounds 9a-d would be able to cross the blood-brain barrier and reach their biological targets in the central nervous system. The promising results in all assays demonstrated that the strategy behind the designing of compounds was rational and favourable. Taken together, these preliminary findings suggested that the compounds with the strongest bioactivity deserves further investigated for pharmacological development in AD therapy.
|
Inhibition of recombinant human MAO-B using kynuramine as substrate after 30 mins by fluorescence assay
|
Homo sapiens
|
44.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : DL-3-n-butylphthalide-Edaravone hybrids as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases with high antioxidant potency for Alzheimer's therapy.
Year : 2017
Volume : 27
Issue : 4
First Page : 718
Last Page : 722
Authors : Qiang X, Li Y, Yang X, Luo L, Xu R, Zheng Y, Cao Z, Tan Z, Deng Y.
Abstract : Considering the complex etiology of Alzheimer's disease (AD), multifunctional agents may be beneficial for the treatment of this disease. A series of DL-3-n-butylphthalide-Edaravone hybrids were designed, synthesized and evaluated as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases. Among them, compounds 9a-d exhibited good inhibition of self-induced Aβ1-42 aggregation with inhibition ratio 57.7-71.5%. For MAO, these new hybrids exhibited good balance of inhibition for MAO-A and MAO-B. In addition, all target compounds retained the antioxidant activity of edaravone, showed equal or better antioxidant activity than edaravone. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compounds 9a-d would be able to cross the blood-brain barrier and reach their biological targets in the central nervous system. The promising results in all assays demonstrated that the strategy behind the designing of compounds was rational and favourable. Taken together, these preliminary findings suggested that the compounds with the strongest bioactivity deserves further investigated for pharmacological development in AD therapy.
|
Irreversible inhibition of human cerebral cortex MAO-A using [14C]-5-hydroxytryptamine creatinine disulphate as substrate pretreated for 60 mins followed by substrate addition after 30 mins by liquid scintillation counting method
|
Homo sapiens
|
710.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of highly selective and potent monoamine oxidase B inhibitors: Contribution of additional phenyl rings introduced into 2-aryl-1,3,4-oxadiazin-5(6H)-one.
Year : 2017
Volume : 130
First Page : 365
Last Page : 378
Authors : Lee J, Lee Y, Park SJ, Lee J, Kim YS, Suh YG, Lee J.
Abstract : Monoamine oxidase B (MAO-B) is a flavin adenine dinucleotide (FAD)-containing enzyme that plays a major role in the oxidative deamination of biogenic amines and neurotransmitters. Inhibiting MAO-B activity is a promising approach in the treatment of neurological disorders. Here, we report a series of 2-aryl-1,3,4-oxadiazin-5(6H)-one derivatives as highly selective and potent MAO-B inhibitors. Analysis of the binding sites of hMAO-A and hMAO-B led to design of linear analogs of 2-aryl-1,3,4-oxadiazin-5(6H)-one with an additional phenyl ring. Biological evaluation of the 26 new derivatives resulted in the identification of highly potent and selective inhibitors with optimal physicochemical properties to potentially cross the blood-brain barrier (BBB). Compounds 18a, 18b, 18e and 25b potently inhibited MAO-B, with IC50 values of 4-25 nM and excellent SI over MAO-A (18a > 25000, 18b > 8333 and 18e > 4000 and 25b > 4545). Docking results suggest that an optimal linker between two aromatic rings on the 2-aryl-1,3,4-oxadiazin-5(6H)-one scaffold is a key element in the binding and inhibition of MAO-B.
|
Irreversible inhibition of human cerebral cortex MAO-B using [14C]-phenylethylamin as substrate pretreated for 60 mins followed by substrate addition after 20 mins by liquid scintillation counting method
|
Homo sapiens
|
14.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of highly selective and potent monoamine oxidase B inhibitors: Contribution of additional phenyl rings introduced into 2-aryl-1,3,4-oxadiazin-5(6H)-one.
Year : 2017
Volume : 130
First Page : 365
Last Page : 378
Authors : Lee J, Lee Y, Park SJ, Lee J, Kim YS, Suh YG, Lee J.
Abstract : Monoamine oxidase B (MAO-B) is a flavin adenine dinucleotide (FAD)-containing enzyme that plays a major role in the oxidative deamination of biogenic amines and neurotransmitters. Inhibiting MAO-B activity is a promising approach in the treatment of neurological disorders. Here, we report a series of 2-aryl-1,3,4-oxadiazin-5(6H)-one derivatives as highly selective and potent MAO-B inhibitors. Analysis of the binding sites of hMAO-A and hMAO-B led to design of linear analogs of 2-aryl-1,3,4-oxadiazin-5(6H)-one with an additional phenyl ring. Biological evaluation of the 26 new derivatives resulted in the identification of highly potent and selective inhibitors with optimal physicochemical properties to potentially cross the blood-brain barrier (BBB). Compounds 18a, 18b, 18e and 25b potently inhibited MAO-B, with IC50 values of 4-25 nM and excellent SI over MAO-A (18a > 25000, 18b > 8333 and 18e > 4000 and 25b > 4545). Docking results suggest that an optimal linker between two aromatic rings on the 2-aryl-1,3,4-oxadiazin-5(6H)-one scaffold is a key element in the binding and inhibition of MAO-B.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate after 30 mins by fluorescence assay
|
Homo sapiens
|
86.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease.
Year : 2017
Volume : 25
Issue : 12
First Page : 3006
Last Page : 3017
Authors : Sang Z, Pan W, Wang K, Ma Q, Yu L, Liu W.
Abstract : A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM-33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC50 values of 0.56μM, 2.3μM, 0.3μM and 1.4μM, respectively) but low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-33 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Furthermore, our investigation proved that TM-33 could cross the blood-brain barrier (BBB) in vitro, and abided by Lipinski's rule of five. The results suggest that compound TM-33, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using tyramine as substrate pretreated for 30 mins followed by substrate addition incubated for 30 mins measured at 5 mins interval by horse-radish peroxidase/amplex red-based fluorometric method
|
Homo sapiens
|
66.0
nM
|
|
Journal : Eur J Med Chem
Title : MAO enzymes inhibitory activity of new benzimidazole derivatives including hydrazone and propargyl side chains.
Year : 2017
Volume : 131
First Page : 92
Last Page : 106
Authors : Can ÖD, Osmaniye D, Demir Özkay Ü, Sağlık BN, Levent S, Ilgın S, Baysal M, Özkay Y, Kaplancıklı ZA.
Abstract : In the present work, 15 new N'-(arylidene)-4-(1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-yl)benzohydrazide (4a-4o) were designed and synthesized. The structures of the synthesized compounds were elucidated using FT-IR, 1H-NMR, 13C-NMR, and HRMS spectral data. The inhibitory activity of the compounds 4a-4o against hMAO-A and hMAO-B enzymes was evaluated by using in vitro Amlex Red® reagent based fluorometric method. Due to lots of high-cost kits including this assay, we determined the ingredients of the kits from the data sheets of several suppliers, and adjusted a protocol by working with various concentrations and volumes of these ingredients. As a result, a fast and sensitive assay was applied as in the commercially available MAO kits with lower costs and clearer ingredients than those of the kits. The enzyme inhibition assay revealed that synthesized compounds have selective inhibition potency against hMAO-B. The compound 4e and 4f displayed IC50 values of 0.075 μM and 0.136 μM against hMAO-B, respectively. The reference drugs selegiline (IC50 = 0.040 μM) and rasagiline (IC50 = 0.066 μM) also displayed a significant inhibition against hMAO-B. The enzyme kinetic study was performed in order to observe the effect of the most active compound 4e on substrate-enzyme relationship and non-competitive inhibition of hMAO-B was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 4e was found as non-cytotoxic and non-genotixic. Theoretical calculation of ADME properties suggested that compound 4e may have a good pharmacokinetic profile. The docking study of compound 4e revealed that there is a strong interaction between the active sites of hMAO-B and analyzed compound.
|
Inhibition of human recombinant microsomal MAOB expressed in baculovirus infected BTI-TN-5B1- 4 cells using p-tyramine as substrate assessed as decrease in H2O2 production after 15 mins by amplex red-based fluorescence assay
|
Homo sapiens
|
49.66
nM
|
|
Journal : J Med Chem
Title : Coumarin versus Chromone Monoamine Oxidase B Inhibitors: Quo Vadis?
Year : 2017
Volume : 60
Issue : 16
First Page : 7206
Last Page : 7212
Authors : Fonseca A, Reis J, Silva T, Matos MJ, Bagetta D, Ortuso F, Alcaro S, Uriarte E, Borges F.
Abstract : Because of the lack of significant disease-modifying drugs for neurodegenerative disorders, a pressing need for new chemical entities endowed with IMAO-B still exists. Within this framework, and for the first time, a study was performed to compare coumarin- and chomone-3-phenylcarboxamide scaffolds. Compounds 10a and 10b were the most potent, selective, and reversible noncompetitive IMAO-B. The benzopyrone sp2 oxygen atom was found to be position independent and a productive contributor for the ligand-enzyme complex stability.
|
Inhibition of human erythrocyte AChE using acetylthiocholine chloride as substrate incubated for 15 mins by Ellman's method
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer's disease.
Year : 2017
Volume : 27
Issue : 22
First Page : 5053
Last Page : 5059
Authors : Sang Z, Wang K, Wang H, Yu L, Wang H, Ma Q, Ye M, Han X, Liu W.
Abstract : A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2μM, 3.8μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate after 30 mins by fluorescence assay
|
Homo sapiens
|
87.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer's disease.
Year : 2017
Volume : 27
Issue : 22
First Page : 5053
Last Page : 5059
Authors : Sang Z, Wang K, Wang H, Yu L, Wang H, Ma Q, Ye M, Han X, Liu W.
Abstract : A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2μM, 3.8μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
|
Inhibition of recombinant human MAO-B using kynuramine as substrate after 30 mins by fluorescence method
|
Homo sapiens
|
86.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of 2-acetyl-5-O-(amino-alkyl)phenol derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2017
Volume : 27
Issue : 22
First Page : 5046
Last Page : 5052
Authors : Sang Z, Wang K, Wang H, Wang H, Ma Q, Han X, Ye M, Yu L, Liu W.
Abstract : A series of 2-acetyl-5-O-(amino-alkyl)phenol derivatives was designed, synthesized and evaluated as multi-function inhibitors for the treatment of Alzheimer's disease (AD). The results revealed that compound TM-3 indicated selective AChE inhibitory potency (eeAChE, IC50 = 0.69 μM, selective index (SI) = 32.7). Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-3 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. And TM-3 was also a highly selective MAO-B inhibitor (IC50 = 6.8 μM). Moreover, TM-3 could act as antioxidant (ORAC value was 1.5eq) and neuroprotectant, as well as a selective metal chelating agent. More interestingly, compound TM-3 could cross the blood-brain barrier (BBB) in vitro and abided by Lipinski's rule of five. Therefore, compound TM-3, a promising multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against AD.
|
Inhibition of recombinant human MAO-B using p-tyramine as substrate preincubated for 15 mins followed by substrate addition measured over 15 mins by Amplex red reagent-based fluorimetric method
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and bioevalucation of novel 2,3-dihydro-1H-inden-1-amine derivatives as potent and selective human monoamine oxidase B inhibitors based on rasagiline.
Year : 2018
Volume : 145
First Page : 588
Last Page : 593
Authors : Xiao X, Zhang XX, Zhan MM, Cheng K, Li S, Xie Z, Liao C.
Abstract : Parkinson's disease (PD) is associated with elevated levels of hMAO-B in the brain, and MAO-B has been recognized a successful target for developing anti-PD drugs. Herein we report rasagiline derivatives as novel potent and selective hMAO-B inhibitors. They were designed by employing fragment-based drug design strategy to link rasagiline and hydrophobic fragments, which may target a hydrophobic pocket in the entrance cavity of hMAO-B. Different linkers such as -OCH2-, -SCH2-, -OCH2CH2-, -OCH2CH2O-, -OCH2CH2CH2O- were tried. A promising selective hMAO-B inhibitor D14 with similar inhibitory activity as rasagiline and improved isoform selectivity was yielded. The selectivity profile of compounds reported herein suggests that we can further develop more potent hMAO-B inhibitors with high isoform selectivity through this strategy.
|
Inhibition of recombinant human MAO-A expressed in baculovirus infected BTI insect cells using kynuramine as substrate after 30 mins by fluorescence assay
|
Homo sapiens
|
587.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment.
Year : 2018
Volume : 26
Issue : 5
First Page : 1102
Last Page : 1115
Authors : Cao Z, Yang J, Xu R, Song Q, Zhang X, Liu H, Qiang X, Li Y, Tan Z, Deng Y.
Abstract : A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate after 30 mins by fluorescence assay
|
Homo sapiens
|
28.1
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of 4'-OH-flurbiprofen-chalcone hybrids as potential multifunctional agents for Alzheimer's disease treatment.
Year : 2018
Volume : 26
Issue : 5
First Page : 1102
Last Page : 1115
Authors : Cao Z, Yang J, Xu R, Song Q, Zhang X, Liu H, Qiang X, Li Y, Tan Z, Deng Y.
Abstract : A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro. Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD.
|
Inhibition of recombinant human MAO-B using kynuramine as substrate after 30 mins by fluorescence assay
|
Homo sapiens
|
83.0
nM
|
|
Journal : Bioorg Med Chem
Title : Multifunctional 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives with acetylcholinesterase, monoamine oxidases and β-amyloid aggregation inhibitory activities as potential agents against Alzheimer's disease.
Year : 2018
Volume : 26
Issue : 8
First Page : 1885
Last Page : 1895
Authors : Xu R, Xiao G, Li Y, Liu H, Song Q, Zhang X, Yang Z, Zheng Y, Tan Z, Deng Y.
Abstract : A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC50 = 0.29 ± 0.01 μM and 0.46 ± 0.02 μM, respectively), MAO-A (IC50 = 8.2 ± 0.08 μM and 7.9 ± 0.07 μM, respectively) and MAO-B (IC50 = 20.1 ± 0.16 μM and 43.8 ± 2.0% at 10 μM, respectively) inhibitory activities, moderate self-induced Aβ1-42 aggregation inhibitory potency (35.4 ± 0.42% and 48.0 ± 1.53% at 25 μM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD.
|
Inhibition of human recombinant MAOB expressed in baculovirus infected BTI-TN-5B1- 4 cells using p-tyramine as substrate assessed as decrease in H2O2 production by amplex red-based fluorescence assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors.
Year : 2018
Volume : 158
First Page : 781
Last Page : 800
Authors : Reis J, Cagide F, Valencia ME, Teixeira J, Bagetta D, Pérez C, Uriarte E, Oliveira PJ, Ortuso F, Alcaro S, Rodríguez-Franco MI, Borges F.
Abstract : There has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi-target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p-methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC50 = 0.21 μM, Ki = 0.19 μM) and displayed dual hMAO inhibitory activity (hMAO-A IC50 = 0.94 μM, Ki = 0.057 μM and hMAO-B IC50 = 3.81 μM, Ki = 0.48 μM). Compound 23a acted as a selective IMAO-B (IC50 = 0.63 μM, Ki = 0.34 μM) while still displaying hChE inhibitory and bifunctional activity in the low micromolar range. Overall, these two compounds stand out as reversible multi-target inhibitors with favourable permeability, toxicological and drug-like profiles, thus being valid candidates for subsequent optimization and pre-clinical studies.
|
Inhibition of recombinant human MAO-A expressed in baculovirus infected BTI insect cells using kynuramine as substrate after 30 mins by fluorescence based assay
|
Homo sapiens
|
587.0
nM
|
|
Journal : Eur J Med Chem
Title : Development of chalcone-O-alkylamine derivatives as multifunctional agents against Alzheimer's disease.
Year : 2019
Volume : 183
First Page : 111737
Last Page : 111737
Authors : Bai P, Wang K, Zhang P, Shi J, Cheng X, Zhang Q, Zheng C, Cheng Y, Yang J, Lu X, Sang Z.
Abstract : A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC50 = 1.3 ± 0.01 μM) and butyrylcholinesterase (IC50 = 1.2 ± 0.09 μM). Besides, 23c exhibited selective MAO-B inhibitory activity with IC50 value of 0.57 ± 0.01 μM. Compound 23c was also a potential antioxidant and neuroprotectant. In addition, compound 23c could inhibit self-induced Aβ1-42 aggregation. Moreover, compound 23c was a selective metal chelator, and could inhibit and disaggregate Cu2+-induced Aβ1-42 aggregation, which was supported by the further transmission electron microscopy images. Furthermore, 23c could cross the blood-brain barrier in vitro, and improved scopolamine-induced memory impairment in vivo assay. Molecular modeling studies showed that 23c could bind to the active site of AChE, BuChE, Aβ1-42 and MAO-B. Taken together, these results suggested that compound 23c might be a potential multifunctional agent for the treatment of AD.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate after 30 mins by fluorescence based assay
|
Homo sapiens
|
28.1
nM
|
|
Journal : Eur J Med Chem
Title : Development of chalcone-O-alkylamine derivatives as multifunctional agents against Alzheimer's disease.
Year : 2019
Volume : 183
First Page : 111737
Last Page : 111737
Authors : Bai P, Wang K, Zhang P, Shi J, Cheng X, Zhang Q, Zheng C, Cheng Y, Yang J, Lu X, Sang Z.
Abstract : A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC50 = 1.3 ± 0.01 μM) and butyrylcholinesterase (IC50 = 1.2 ± 0.09 μM). Besides, 23c exhibited selective MAO-B inhibitory activity with IC50 value of 0.57 ± 0.01 μM. Compound 23c was also a potential antioxidant and neuroprotectant. In addition, compound 23c could inhibit self-induced Aβ1-42 aggregation. Moreover, compound 23c was a selective metal chelator, and could inhibit and disaggregate Cu2+-induced Aβ1-42 aggregation, which was supported by the further transmission electron microscopy images. Furthermore, 23c could cross the blood-brain barrier in vitro, and improved scopolamine-induced memory impairment in vivo assay. Molecular modeling studies showed that 23c could bind to the active site of AChE, BuChE, Aβ1-42 and MAO-B. Taken together, these results suggested that compound 23c might be a potential multifunctional agent for the treatment of AD.
|
Inhibition of MAO-A in rat brain using [14C]-5-hydroxytryptamine creatinine disulfate as substrate preincubated for 60 mins followed by substrate addition and measured after 30 mins by liquid scintillation counting method
|
Rattus norvegicus
|
410.0
nM
|
|
Journal : J Med Chem
Title : Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms.
Year : 2019
Volume : 62
Issue : 20
First Page : 8881
Last Page : 8914
Authors : Zhou J, Jiang X, He S, Jiang H, Feng F, Liu W, Qu W, Sun H.
Abstract : Due to the complexity of multifactorial diseases, single-target drugs do not always exhibit satisfactory efficacy. Recently, increasing evidence indicates that simultaneous modulation of multiple targets may improve both therapeutic safety and efficacy, compared with single-target drugs. However, few multitarget drugs are on market or in clinical trials, despite the best efforts of medicinal chemists. This article discusses the systematic establishment of target combination, lead generation, and optimization of multitarget-directed ligands (MTDLs). Moreover, we analyze some MTDLs research cases for several complex diseases in recent years and the physicochemical properties of 117 clinical multitarget drugs, with the aim to reveal the trends and insights of the potential use of MTDLs.
|
Inhibition of MAO-B in rat brain using [14C]-phenylethylamine as substrate preincubated for 60 mins followed by substrate addition and measured after 30 mins by liquid scintillation counting method
|
Rattus norvegicus
|
4.4
nM
|
|
Journal : J Med Chem
Title : Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms.
Year : 2019
Volume : 62
Issue : 20
First Page : 8881
Last Page : 8914
Authors : Zhou J, Jiang X, He S, Jiang H, Feng F, Liu W, Qu W, Sun H.
Abstract : Due to the complexity of multifactorial diseases, single-target drugs do not always exhibit satisfactory efficacy. Recently, increasing evidence indicates that simultaneous modulation of multiple targets may improve both therapeutic safety and efficacy, compared with single-target drugs. However, few multitarget drugs are on market or in clinical trials, despite the best efforts of medicinal chemists. This article discusses the systematic establishment of target combination, lead generation, and optimization of multitarget-directed ligands (MTDLs). Moreover, we analyze some MTDLs research cases for several complex diseases in recent years and the physicochemical properties of 117 clinical multitarget drugs, with the aim to reveal the trends and insights of the potential use of MTDLs.
|
Inhibition of recombinant human microsomal MAOB expressed in baculovirus infected BTI insect cells using p-tyramine as substrate preincubated for 15 mins followed by substrate addition and measured over 20 mins by amplex red reagent-based horseradish peroxidase-coupled fluorometric assay
|
Homo sapiens
|
36.0
nM
|
|
Journal : J Med Chem
Title : Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B.
Year : 2020
Volume : 63
Issue : 3
First Page : 1361
Last Page : 1387
Authors : Knez D, Colettis N, Iacovino LG, Sova M, Pišlar A, Konc J, Lešnik S, Higgs J, Kamecki F, Mangialavori I, Dolšak A, Žakelj S, Trontelj J, Kos J, Binda C, Marder M, Gobec S.
Abstract : The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.
|
Inhibition of human MAO-B expressed in baculovirus infected BTI insect cells using p-tyramine as substrate preincubated for 30 mins followed by substrate addition and measured after 1 hr by fluorescence-based Amplex Red MAO assay
|
Homo sapiens
|
25.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : 4-tert-Pentylphenoxyalkyl derivatives - Histamine H<sub>3</sub> receptor ligands and monoamine oxidase B inhibitors.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3596
Last Page : 3600
Authors : Łażewska D, Olejarz-Maciej A, Kaleta M, Bajda M, Siwek A, Karcz T, Doroz-Płonka A, Cichoń U, Kuder K, Kieć-Kononowicz K.
Abstract : The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H<sub>3</sub> receptor affinity with K<sub>i</sub> values below 760 nM. The inhibitory activity toward human monoamine oxidase B (hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the compounds were effective in the submicromolar range. Among them, 1-(3-(4-tert-pPentylphenoxy)propyl)pyrrolidine (5) exhibited hMAO B inhibitory activity with an IC<sub>50</sub> value of 4.5 nM. In addition, hMAO B inhibition by 5 was shown to be non-competitive and reversible. Further, recently described potent histamine H<sub>3</sub> receptor ligands - 4-tert-pentylphenoxyalkyl derivatives (with a 4-8 carbon spacer) - were evaluated for hMAO B inhibitory activity, and some of them displayed activity in the submicromolar range. Selected compounds were also tested for human MAO A (hMAO A) inhibitory potencies and exhibited no activity. Moreover, molecular modeling studies were carried out for tested compounds to explain their molecular mechanism of hMAO B inhibition and the selectivity of compounds for hMAO B over hMAO A.
|
Irreversible inhibition of human MAOB
|
Homo sapiens
|
14.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : 4-tert-Pentylphenoxyalkyl derivatives - Histamine H<sub>3</sub> receptor ligands and monoamine oxidase B inhibitors.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3596
Last Page : 3600
Authors : Łażewska D, Olejarz-Maciej A, Kaleta M, Bajda M, Siwek A, Karcz T, Doroz-Płonka A, Cichoń U, Kuder K, Kieć-Kononowicz K.
Abstract : The synthesis and biological activity of 4-tert-pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H<sub>3</sub> receptor affinity with K<sub>i</sub> values below 760 nM. The inhibitory activity toward human monoamine oxidase B (hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the compounds were effective in the submicromolar range. Among them, 1-(3-(4-tert-pPentylphenoxy)propyl)pyrrolidine (5) exhibited hMAO B inhibitory activity with an IC<sub>50</sub> value of 4.5 nM. In addition, hMAO B inhibition by 5 was shown to be non-competitive and reversible. Further, recently described potent histamine H<sub>3</sub> receptor ligands - 4-tert-pentylphenoxyalkyl derivatives (with a 4-8 carbon spacer) - were evaluated for hMAO B inhibitory activity, and some of them displayed activity in the submicromolar range. Selected compounds were also tested for human MAO A (hMAO A) inhibitory potencies and exhibited no activity. Moreover, molecular modeling studies were carried out for tested compounds to explain their molecular mechanism of hMAO B inhibition and the selectivity of compounds for hMAO B over hMAO A.
|
Inhibition of recombinant human MAO-A expressed in baculovirus infected BTI insect cells using p-tyramine as substrate preincubated for 60 mins followed by substrate addition and measured after 30 mins by horse-radish peroxidase-coupled amplex red reagent-based fluorescence spectrophotometric method
|
Homo sapiens
|
750.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of coumarin Mannich base derivatives as multifunctional agents against monoamine oxidase B and neuroinflammation for the treatment of Parkinson's disease.
Year : 2019
Volume : 173
First Page : 203
Last Page : 212
Authors : Tao D, Wang Y, Bao XQ, Yang BB, Gao F, Wang L, Zhang D, Li L.
Abstract : Due to the complexity of the pathogenesis of Parkinson's disease (PD), multimodal treatment may achieve better results. In this study, a series of coumarin Mannich base derivatives were designed and synthesized as multifunctional agents for PD treatment. Among the derivatives, 3-(3-(dimethylamino)propanoyl)-7-hydroxy-5-methyl- 2H-chromen-2-one hydrochloride (24) exhibited the most potent and selective hMAO-B inhibitory activity, and anti-inflammatory and neuroprotective effects in the in vitro studies. It significantly attenuated PD-associated behavioural deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Furthermore, preliminary mechanistic studies indicated that 24 could selectively inhibit MAO-B activity, decrease the neuroinflammatory process, and protect tyrosine hydroxylase-immunopositive dopaminergic neurons. These results suggest that 24 is a promising multifunctional agent for effective therapy for PD.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using p-tyramine as substrate preincubated for 60 mins followed by substrate addition and measured after 30 mins by horse-radish peroxidase-coupled amplex red reagent-based fluorescence spectrophotometric method
|
Homo sapiens
|
8.4
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of coumarin Mannich base derivatives as multifunctional agents against monoamine oxidase B and neuroinflammation for the treatment of Parkinson's disease.
Year : 2019
Volume : 173
First Page : 203
Last Page : 212
Authors : Tao D, Wang Y, Bao XQ, Yang BB, Gao F, Wang L, Zhang D, Li L.
Abstract : Due to the complexity of the pathogenesis of Parkinson's disease (PD), multimodal treatment may achieve better results. In this study, a series of coumarin Mannich base derivatives were designed and synthesized as multifunctional agents for PD treatment. Among the derivatives, 3-(3-(dimethylamino)propanoyl)-7-hydroxy-5-methyl- 2H-chromen-2-one hydrochloride (24) exhibited the most potent and selective hMAO-B inhibitory activity, and anti-inflammatory and neuroprotective effects in the in vitro studies. It significantly attenuated PD-associated behavioural deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Furthermore, preliminary mechanistic studies indicated that 24 could selectively inhibit MAO-B activity, decrease the neuroinflammatory process, and protect tyrosine hydroxylase-immunopositive dopaminergic neurons. These results suggest that 24 is a promising multifunctional agent for effective therapy for PD.
|
Inhibition of human recombinant MAO-A expressed in baculovirus infected BTI-TN-5B1-4 insect cells assessed as decrease in H2O2 production using p-tyramine as substrate incubated for 20 mins by horse-radish peroxidase/amplex red-based fluorescence method
|
Homo sapiens
|
680.0
nM
|
|
Journal : Eur J Med Chem
Title : Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors.
Year : 2019
Volume : 179
First Page : 404
Last Page : 422
Authors : Tzvetkov NT, Stammler HG, Georgieva MG, Russo D, Faraone I, Balacheva AA, Hristova S, Atanasov AG, Milella L, Antonov L, Gastreich M.
Abstract : A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11-16) and (indazole-5-yl)methanimines (17-22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ± 1.7 μM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17-22 as the amide spacer in their carboxamide analogs 11-16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells assessed as decrease in H2O2 production using p-tyramine as substrate incubated for 20 mins by horse-radish peroxidase/amplex red-based fluorescence method
|
Homo sapiens
|
13.0
nM
|
|
Journal : Eur J Med Chem
Title : Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors.
Year : 2019
Volume : 179
First Page : 404
Last Page : 422
Authors : Tzvetkov NT, Stammler HG, Georgieva MG, Russo D, Faraone I, Balacheva AA, Hristova S, Atanasov AG, Milella L, Antonov L, Gastreich M.
Abstract : A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11-16) and (indazole-5-yl)methanimines (17-22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ± 1.7 μM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17-22 as the amide spacer in their carboxamide analogs 11-16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.
|
Inhibition of human recombinant MAO-A using kynuramine as substrate measured after 30 mins by fluorimetric assay
|
Homo sapiens
|
630.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2019
Volume : 29
Issue : 19
First Page : 126625
Last Page : 126625
Authors : Zhu G, Wang K, Shi J, Zhang P, Yang D, Fan X, Zhang Z, Liu W, Sang Z.
Abstract : A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC<sub>50</sub> value of 2.9 μM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that TM-14 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound TM-14 was a selective metal chelator and could form 1:1 TM-14-Cu<sup>2+</sup> complex. The structure-active-relationship also indicated that the O-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound TM-2 exhibited potent hMAO-B inhibitory activity (IC<sub>50</sub> = 6.8 μM), which was supported by the molecular docking study. More interestingly, compounds TM-14 and TM-2 could cross the blood-brain barrier in vitro. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer's disease.
|
Inhibition of human recombinant MAO-B using kynuramine as substrate measured after 30 mins by fluorimetric assay
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2019
Volume : 29
Issue : 19
First Page : 126625
Last Page : 126625
Authors : Zhu G, Wang K, Shi J, Zhang P, Yang D, Fan X, Zhang Z, Liu W, Sang Z.
Abstract : A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC<sub>50</sub> value of 2.9 μM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that TM-14 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound TM-14 was a selective metal chelator and could form 1:1 TM-14-Cu<sup>2+</sup> complex. The structure-active-relationship also indicated that the O-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound TM-2 exhibited potent hMAO-B inhibitory activity (IC<sub>50</sub> = 6.8 μM), which was supported by the molecular docking study. More interestingly, compounds TM-14 and TM-2 could cross the blood-brain barrier in vitro. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer's disease.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate measured after 30 mins by fluorescence based assay
|
Homo sapiens
|
31.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, in-silico and biological evaluation of novel chalcone-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2019
Volume : 178
First Page : 726
Last Page : 739
Authors : Sang Z, Wang K, Shi J, Liu W, Tan Z.
Abstract : To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aβ<sub>1-42</sub> aggregation inhibition, metal-chelating properties and neuroprotective effects against H<sub>2</sub>O<sub>2</sub>-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC<sub>50</sub> values of 3.1 μM and 1.2 μM, respectively and showed highly selective MAO-B inhibitory potency with IC<sub>50</sub> values of 1.3 μM and 3.7 μM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aβ<sub>1-42</sub> aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu<sup>2+</sup> and Al<sup>3+</sup>. Moreover, compound 5b could inhibit and disaggregate Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization.
|
Inhibition of recombinant human MAO-A expressed in baculovirus infected BTI insect cells using kynuramine as substrate measured after 30 mins by fluorescence based assay
|
Homo sapiens
|
620.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, in-silico and biological evaluation of novel chalcone-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer's disease.
Year : 2019
Volume : 178
First Page : 726
Last Page : 739
Authors : Sang Z, Wang K, Shi J, Liu W, Tan Z.
Abstract : To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aβ<sub>1-42</sub> aggregation inhibition, metal-chelating properties and neuroprotective effects against H<sub>2</sub>O<sub>2</sub>-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC<sub>50</sub> values of 3.1 μM and 1.2 μM, respectively and showed highly selective MAO-B inhibitory potency with IC<sub>50</sub> values of 1.3 μM and 3.7 μM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aβ<sub>1-42</sub> aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu<sup>2+</sup> and Al<sup>3+</sup>. Moreover, compound 5b could inhibit and disaggregate Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization.
|
Inhibition of recombinant human MAO-A expressed in baculovirus infected BTI insect cells using kynuramine as substrate incubated for 30 mins by fluorescence based assay
|
Homo sapiens
|
587.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, in-silico and biological evaluation of novel chalcone derivatives as multi-function agents for the treatment of Alzheimer's disease.
Year : 2019
Volume : 180
First Page : 238
Last Page : 252
Authors : Sang Z, Wang K, Zhang P, Shi J, Liu W, Tan Z.
Abstract : A series of novel chalcone derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of AD. Among of these synthesized compounds, compound TM-2 was a selective BuChE inhibitor (IC<sub>50</sub> = 2.6 μM) and selective MAO-B inhibitor (IC<sub>50</sub> = 5.3 μM), which were supported by docking study. Compound TM-2 also showed good antioxidant activity, and was a selective metal chelator, as well as a neuroprotectant. Moreover, compound TM-2 could significantly inhibit self-induced and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation with 70.2% and 80.7% inhibition rate, respectively, and could disaggregate Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation (73.5%), the further TEM images observed provided rational explanation. Besides, compound TM-2 displayed good PAMPA-BBB permeability and conformed to the Lipinski's rule of five. Further, compound TM-2 presented precognitive effect on scopolamine-induced memory impairment in vivo assay. Therefore, compound TM-2 might be a promising multifunctional hit compound for the treatment of AD, and the further structure optimization are in progress.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate incubated for 30 mins by fluorescence based assay
|
Homo sapiens
|
28.1
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, in-silico and biological evaluation of novel chalcone derivatives as multi-function agents for the treatment of Alzheimer's disease.
Year : 2019
Volume : 180
First Page : 238
Last Page : 252
Authors : Sang Z, Wang K, Zhang P, Shi J, Liu W, Tan Z.
Abstract : A series of novel chalcone derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of AD. Among of these synthesized compounds, compound TM-2 was a selective BuChE inhibitor (IC<sub>50</sub> = 2.6 μM) and selective MAO-B inhibitor (IC<sub>50</sub> = 5.3 μM), which were supported by docking study. Compound TM-2 also showed good antioxidant activity, and was a selective metal chelator, as well as a neuroprotectant. Moreover, compound TM-2 could significantly inhibit self-induced and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation with 70.2% and 80.7% inhibition rate, respectively, and could disaggregate Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation (73.5%), the further TEM images observed provided rational explanation. Besides, compound TM-2 displayed good PAMPA-BBB permeability and conformed to the Lipinski's rule of five. Further, compound TM-2 presented precognitive effect on scopolamine-induced memory impairment in vivo assay. Therefore, compound TM-2 might be a promising multifunctional hit compound for the treatment of AD, and the further structure optimization are in progress.
|
Inhibition of Sprague-Dawley rat liver MAO-A using p-tyramine as substrate preincubated for 15 mins and measured after 45 mins by resorufin-based fluorescence assay
|
Rattus norvegicus
|
422.0
nM
|
|
Journal : Eur J Med Chem
Title : (Pyrrolo-pyridin-5-yl)benzamides: BBB permeable monoamine oxidase B inhibitors with neuroprotective effect on cortical neurons.
Year : 2019
Volume : 162
First Page : 793
Last Page : 809
Authors : Tzvetkov NT, Stammler HG, Hristova S, Atanasov AG, Antonov L.
Abstract : An extensive study was performed to develop a series of (pyrrolo-pyridin-5-yl)benzamides as reversible MAO-B inhibitors. Compounds 14 (NTZ-2020, hMAO-B IC<sub>50</sub> = 1.11 nM, K<sub>i</sub> = 0.56 nM, >9000-fold selective versus MAO-A) and 15 (NTZ-2027, hMAO-B IC<sub>50</sub> = 3.27 nM, K<sub>i</sub> = 1.45 nM, SI > 3058) are identified as the most promising BBB permeable derivatives within the series of (1H-pyrrolo[3,2-b]pyridine-5-yl)benzamides, combining both high potency and selectivity with optimal physicochemical and drug-like properties required for CNS active drugs. Extended photophysical analysis, including single X-ray analysis, quantum-chemical calculations and spectroscopic experiments provided insights into their tautomerism and structural behavioral, which relates to their biologically active form. The reversible MAO-B inhibitor 14 (NTZ-2020) exhibits a neuroprotective effect on cortical neuron survival and induces neurite network outgrowth. These effects are associated with a good BBB penetration of 14 that was confirmed in a triple cell neurovascular unit (NVU) model.
|
Inhibition of human recombinant MAO-A expressed in baculovirus infected BTI-TN-5B1-4 insect cells using p-tyramine as substrate preincubated for 15 mins and measured after 45 mins by resorufin-based fluorescence assay
|
Homo sapiens
|
680.0
nM
|
|
Journal : Eur J Med Chem
Title : (Pyrrolo-pyridin-5-yl)benzamides: BBB permeable monoamine oxidase B inhibitors with neuroprotective effect on cortical neurons.
Year : 2019
Volume : 162
First Page : 793
Last Page : 809
Authors : Tzvetkov NT, Stammler HG, Hristova S, Atanasov AG, Antonov L.
Abstract : An extensive study was performed to develop a series of (pyrrolo-pyridin-5-yl)benzamides as reversible MAO-B inhibitors. Compounds 14 (NTZ-2020, hMAO-B IC<sub>50</sub> = 1.11 nM, K<sub>i</sub> = 0.56 nM, >9000-fold selective versus MAO-A) and 15 (NTZ-2027, hMAO-B IC<sub>50</sub> = 3.27 nM, K<sub>i</sub> = 1.45 nM, SI > 3058) are identified as the most promising BBB permeable derivatives within the series of (1H-pyrrolo[3,2-b]pyridine-5-yl)benzamides, combining both high potency and selectivity with optimal physicochemical and drug-like properties required for CNS active drugs. Extended photophysical analysis, including single X-ray analysis, quantum-chemical calculations and spectroscopic experiments provided insights into their tautomerism and structural behavioral, which relates to their biologically active form. The reversible MAO-B inhibitor 14 (NTZ-2020) exhibits a neuroprotective effect on cortical neuron survival and induces neurite network outgrowth. These effects are associated with a good BBB penetration of 14 that was confirmed in a triple cell neurovascular unit (NVU) model.
|
Inhibition of Sprague-Dawley rat liver MAO-B using p-tyramine as substrate preincubated for 15 mins and measured after 45 mins by resorufin-based fluorescence assay
|
Rattus norvegicus
|
4.31
nM
|
|
Journal : Eur J Med Chem
Title : (Pyrrolo-pyridin-5-yl)benzamides: BBB permeable monoamine oxidase B inhibitors with neuroprotective effect on cortical neurons.
Year : 2019
Volume : 162
First Page : 793
Last Page : 809
Authors : Tzvetkov NT, Stammler HG, Hristova S, Atanasov AG, Antonov L.
Abstract : An extensive study was performed to develop a series of (pyrrolo-pyridin-5-yl)benzamides as reversible MAO-B inhibitors. Compounds 14 (NTZ-2020, hMAO-B IC<sub>50</sub> = 1.11 nM, K<sub>i</sub> = 0.56 nM, >9000-fold selective versus MAO-A) and 15 (NTZ-2027, hMAO-B IC<sub>50</sub> = 3.27 nM, K<sub>i</sub> = 1.45 nM, SI > 3058) are identified as the most promising BBB permeable derivatives within the series of (1H-pyrrolo[3,2-b]pyridine-5-yl)benzamides, combining both high potency and selectivity with optimal physicochemical and drug-like properties required for CNS active drugs. Extended photophysical analysis, including single X-ray analysis, quantum-chemical calculations and spectroscopic experiments provided insights into their tautomerism and structural behavioral, which relates to their biologically active form. The reversible MAO-B inhibitor 14 (NTZ-2020) exhibits a neuroprotective effect on cortical neuron survival and induces neurite network outgrowth. These effects are associated with a good BBB penetration of 14 that was confirmed in a triple cell neurovascular unit (NVU) model.
|
Inhibition of human recombinant MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells using p-tyramine as substrate preincubated for 15 mins and measured after 45 mins by resorufin-based fluorescence assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : Eur J Med Chem
Title : (Pyrrolo-pyridin-5-yl)benzamides: BBB permeable monoamine oxidase B inhibitors with neuroprotective effect on cortical neurons.
Year : 2019
Volume : 162
First Page : 793
Last Page : 809
Authors : Tzvetkov NT, Stammler HG, Hristova S, Atanasov AG, Antonov L.
Abstract : An extensive study was performed to develop a series of (pyrrolo-pyridin-5-yl)benzamides as reversible MAO-B inhibitors. Compounds 14 (NTZ-2020, hMAO-B IC<sub>50</sub> = 1.11 nM, K<sub>i</sub> = 0.56 nM, >9000-fold selective versus MAO-A) and 15 (NTZ-2027, hMAO-B IC<sub>50</sub> = 3.27 nM, K<sub>i</sub> = 1.45 nM, SI > 3058) are identified as the most promising BBB permeable derivatives within the series of (1H-pyrrolo[3,2-b]pyridine-5-yl)benzamides, combining both high potency and selectivity with optimal physicochemical and drug-like properties required for CNS active drugs. Extended photophysical analysis, including single X-ray analysis, quantum-chemical calculations and spectroscopic experiments provided insights into their tautomerism and structural behavioral, which relates to their biologically active form. The reversible MAO-B inhibitor 14 (NTZ-2020) exhibits a neuroprotective effect on cortical neuron survival and induces neurite network outgrowth. These effects are associated with a good BBB penetration of 14 that was confirmed in a triple cell neurovascular unit (NVU) model.
|
Inhibition of rat brain MAO-B using [14C]-phenylethylamine as substrate preincubated for 60 mins followed by substrate addition and measured after 20 mins by liquid scintillation counting method
|
Rattus norvegicus
|
4.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Rasagiline derivatives combined with histamine H<sub>3</sub> receptor properties.
Year : 2019
Volume : 29
Issue : 19
First Page : 126612
Last Page : 126612
Authors : Lutsenko K, Hagenow S, Affini A, Reiner D, Stark H.
Abstract : The irreversible monoamine oxidase B (MAO B) inhibitor rasagiline has been described with multiple disease modifying effects in vitro on models of Parkinson's disease. The combination of this established drug to recently developed histamine H<sub>3</sub> receptor (H<sub>3</sub>R) antagonist elements gives new impetus to the design of multitargeting ligands. Surprisingly, the 5-substituted 3-piperidinopropyloxy rasagiline derivative 1 was more potent on both targets than its 6-substituted isomer. It showed nanomolar affinities at the desired targets (MAO B IC<sub>50</sub> = 256 nM; hH<sub>3</sub>R K<sub>i</sub> = 2.6 nM) with a high preference over monoamine oxidase A (MAO A) and negligible affinity at histamine H<sub>1</sub>, H<sub>4</sub>, dopamine D<sub>2</sub>, D<sub>3</sub> receptors or acetyl-/butyrylcholinesterases.
|
Inhibition of human microsomal MAO-B expressed in recombinant baculovirus infected insect BTI-TN-5B1-4 cells assessed as reduction in H2O2 production using p-tyramine as substrate after 15 mins by fluorescence assay
|
Homo sapiens
|
49.66
nM
|
|
Inhibition of human microsomal MAO-B expressed in recombinant baculovirus infected insect BTI-TN-5B1-4 cells assessed as reduction in H2O2 production using p-tyramine as substrate after 15 mins by fluorescence assay
|
Homo sapiens
|
50.12
nM
|
|
Journal : J Med Chem
Title : Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors.
Year : 2016
Volume : 59
Issue : 12
First Page : 5879
Last Page : 5893
Authors : Reis J, Cagide F, Chavarria D, Silva T, Fernandes C, Gaspar A, Uriarte E, Remião F, Alcaro S, Ortuso F, Borges F.
Abstract : The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3'-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3',4'-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood-brain barrier permeability, thus being a valid candidate for subsequent animal studies.
|
Inhibition of MAO-B in Wistar rat liver using 4-trifluoromethyl benzylamine as substrate preincubated for 20 mins followed by substrate addition measured after 90 mins by microplate reader assay
|
Rattus norvegicus
|
230.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and biological evaluation of 4-arylcoumarins as potential anti-Alzheimer's disease agents.
Year : 2020
Volume : 30
Issue : 4
First Page : 126900
Last Page : 126900
Authors : Yun Y, Yang J, Miao Y, Wang X, Sun J.
Abstract : Alzheimer's disease (AD) is a progressive neurological degenerative disease that has complex pathogenesis. A variety of studies in humans indicate that several enzymes inhibitors can be useful in the treatment of AD, including acetylcholinesterase (AchE), butyrylcholinesterase (BuChE) and monoamine oxidase (MAO). Various substituted 4-arylcoumarin derivatives were synthesised, and their activity in vitro were investigated, including AChE/BuChE inhibitory activity, MAO inhibitory activity, and antioxidant activity. Most of the compounds were found to exhibit high inhibitory activity, and individual compounds have extremely excellent activities. Therefore 4-arylcoumarins provides an idea for drugs design for the development of therapeutic or preventive agents for AD.
|
Inhibition of recombinant human MAO-A expressed in baculovirus infected BTI insect cells using kynuramine as substrate measured after 30 mins by fluorescence based assay
|
Homo sapiens
|
712.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of phthalide alkyl tertiary amine derivatives as promising acetylcholinesterase inhibitors with high potency and selectivity against Alzheimer's disease.
Year : 2020
Volume : 28
Issue : 8
First Page : 115400
Last Page : 115400
Authors : Luo L, Song Q, Li Y, Cao Z, Qiang X, Tan Z, Deng Y.
Abstract : A series of phthalide alkyl tertiary amine derivatives were designed, synthesized and evaluated as potential multi-target agents against Alzheimer's disease (AD). The results indicated that almost all the compounds displayed significant AChE inhibitory and selective activities. Besides, most of the derivatives exhibited increased self-induced Aβ<sub>1-42</sub> aggregation inhibitory activity compared to the lead compound dl-NBP, and some compounds also exerted good antioxidant activity. Specifically, compound I-8 showed the highest inhibitory potency toward AChE (IC<sub>50</sub> = 2.66 nM), which was significantly better than Donepezil (IC<sub>50</sub> = 26.4 nM). Moreover, molecular docking studies revealed that compound I-8 could bind to both the catalytic active site and peripheral anionic site of AChE. Furthermore, compound I-8 displayed excellent BBB permeability in vitro. Importantly, the step-down passive avoidance test indicated that I-8 significantly reversed scopolamine-induced memory deficit in mice. Collectively, these results suggested that I-8 might be a potent and selective AChE inhibitor for further anti-AD drug development.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using kynuramine as substrate measured after 30 mins by fluorescence based assay
|
Homo sapiens
|
43.7
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of phthalide alkyl tertiary amine derivatives as promising acetylcholinesterase inhibitors with high potency and selectivity against Alzheimer's disease.
Year : 2020
Volume : 28
Issue : 8
First Page : 115400
Last Page : 115400
Authors : Luo L, Song Q, Li Y, Cao Z, Qiang X, Tan Z, Deng Y.
Abstract : A series of phthalide alkyl tertiary amine derivatives were designed, synthesized and evaluated as potential multi-target agents against Alzheimer's disease (AD). The results indicated that almost all the compounds displayed significant AChE inhibitory and selective activities. Besides, most of the derivatives exhibited increased self-induced Aβ<sub>1-42</sub> aggregation inhibitory activity compared to the lead compound dl-NBP, and some compounds also exerted good antioxidant activity. Specifically, compound I-8 showed the highest inhibitory potency toward AChE (IC<sub>50</sub> = 2.66 nM), which was significantly better than Donepezil (IC<sub>50</sub> = 26.4 nM). Moreover, molecular docking studies revealed that compound I-8 could bind to both the catalytic active site and peripheral anionic site of AChE. Furthermore, compound I-8 displayed excellent BBB permeability in vitro. Importantly, the step-down passive avoidance test indicated that I-8 significantly reversed scopolamine-induced memory deficit in mice. Collectively, these results suggested that I-8 might be a potent and selective AChE inhibitor for further anti-AD drug development.
|
Inhibition of recombinant human MAOB expressed in baculovirus infected in BTI cells using kynuramine as substrate after 30 mins by fluorescence based assay
|
Homo sapiens
|
11.6
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of flurbiprofen-clioquinol hybrids as multitarget-directed ligands against Alzheimer's disease.
Year : 2020
Volume : 28
Issue : 7
First Page : 115374
Last Page : 115374
Authors : Yang Z, Song Q, Cao Z, Yu G, Liu Z, Tan Z, Deng Y.
Abstract : A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu<sup>2+</sup>-induced β-amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r, also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment.
|
Inhibition of recombinant human MAO-A
|
Homo sapiens
|
32.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease.
Year : 2020
Volume : 194
First Page : 112265
Last Page : 112265
Authors : Sang Z,Wang K,Bai P,Wu A,Shi J,Liu W,Zhu G,Wang Y,Lan Y,Chen Z,Zhao Y,Qiao Z,Wang C,Tan Z
Abstract : A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC value of 0.97 μM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC = 5.3 μM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Aβ aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AlCl-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Aβ. PET-CT imaging demonstrated that [C]4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease.
|
Inhibition of recombinant human MAO-B
|
Homo sapiens
|
530.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel O-carbamoyl ferulamide derivatives as multi-target-directed ligands for the treatment of Alzheimer's disease.
Year : 2020
Volume : 194
First Page : 112265
Last Page : 112265
Authors : Sang Z,Wang K,Bai P,Wu A,Shi J,Liu W,Zhu G,Wang Y,Lan Y,Chen Z,Zhao Y,Qiao Z,Wang C,Tan Z
Abstract : A novel series of O-carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible hBChE (human butyrylcholinesterase) inhibitor with an IC value of 0.97 μM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC = 5.3 μM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Aβ aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AlCl-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Aβ. PET-CT imaging demonstrated that [C]4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI cells using p-tyramine as substrate by fluorometric assay
|
Homo sapiens
|
25.0
nM
|
|
Journal : Eur J Med Chem
Title : Rational design of new multitarget histamine H receptor ligands as potential candidates for treatment of Alzheimer's disease.
Year : 2020
Volume : 207
First Page : 112743
Last Page : 112743
Authors : Łażewska D,Bajda M,Kaleta M,Zaręba P,Doroz-Płonka A,Siwek A,Alachkar A,Mogilski S,Saad A,Kuder K,Olejarz-Maciej A,Godyń J,Stary D,Sudoł S,Więcek M,Latacz G,Walczak M,Handzlik J,Sadek B,Malawska B,Kieć-Kononowicz K
Abstract : Design and development of multitarget-directed ligands (MTDLs) has become a very important approach in the search of new therapies for Alzheimer's disease (AD). In our present research, a number of xanthone derivatives were first designed using a pharmacophore model for histamine H receptor (HR) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human HR (hHR) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hHR affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC values in submicromolar range. Furthermore, the inhibitory effects of monoamine oxidases (MAO) A and B were investigated. The results showed low micromolar and selective human MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7-chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hHR (K = 170 nM and 100 nM respectively) and high inhibitory activity for acetylcholinesterase (IC = 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC = 880 nM and 394 nM respectively) and hMAO B (IC = 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hHR, human cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for in vivo studies. The results showed significant memory-enhancing effect of compound 23 in dizocilpine-induced amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable analgesic effects of compound 23 were observed in neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.
|
Displacement of [3H]-LSD from human 5HT6 receptor expressed in HEK293 cells measured after 1 hr by microbeta plate reader method
|
Homo sapiens
|
1.4
nM
|
|
Journal : Eur J Med Chem
Title : A dual-acting 5-HT receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties.
Year : 2020
Volume : 208
First Page : 112765
Last Page : 112765
Authors : Canale V,Grychowska K,Kurczab R,Ryng M,Keeri AR,Satała G,Olejarz-Maciej A,Koczurkiewicz P,Drop M,Blicharz K,Piska K,Pękala E,Janiszewska P,Krawczyk M,Walczak M,Chaumont-Dubel S,Bojarski AJ,Marin P,Popik P,Zajdel P
Abstract : The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT receptor (5-HTR) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HTR with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HTR at G signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HTR/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells using p-tyramine as substrate preincubated for 30 mins followed by substrate addition and measured after 1 hr by fluorimetric analysis
|
Homo sapiens
|
15.4
nM
|
|
Journal : Eur J Med Chem
Title : A dual-acting 5-HT receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties.
Year : 2020
Volume : 208
First Page : 112765
Last Page : 112765
Authors : Canale V,Grychowska K,Kurczab R,Ryng M,Keeri AR,Satała G,Olejarz-Maciej A,Koczurkiewicz P,Drop M,Blicharz K,Piska K,Pękala E,Janiszewska P,Krawczyk M,Walczak M,Chaumont-Dubel S,Bojarski AJ,Marin P,Popik P,Zajdel P
Abstract : The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT receptor (5-HTR) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HTR with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HTR at G signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HTR/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI insect cells at 1 uM using p-tyramine as substrate preincubated for 30 mins followed by substrate addition and measured after 1 hr by fluorimetric analysis relative to control
|
Homo sapiens
|
100.0
%
|
|
Journal : Eur J Med Chem
Title : A dual-acting 5-HT receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties.
Year : 2020
Volume : 208
First Page : 112765
Last Page : 112765
Authors : Canale V,Grychowska K,Kurczab R,Ryng M,Keeri AR,Satała G,Olejarz-Maciej A,Koczurkiewicz P,Drop M,Blicharz K,Piska K,Pękala E,Janiszewska P,Krawczyk M,Walczak M,Chaumont-Dubel S,Bojarski AJ,Marin P,Popik P,Zajdel P
Abstract : The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT receptor (5-HTR) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HTR with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HTR at G signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HTR/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.
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Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI-TN-5B1-4 insect cells using p-tyramine as substrate preincubated for 15 mins followed by substrate addition and measured over 20 mins by horse-radish peroxidase/Amplex Red coupled fluorimetric analysis
|
Homo sapiens
|
36.0
nM
|
|
Journal : Eur J Med Chem
Title : Pyrimido[1,2-b]indazole derivatives: Selective inhibitors of human monoamine oxidase B with neuroprotective activity.
Year : 2021
Volume : 209
First Page : 112911
Last Page : 112911
Authors : Jismy B,El Qami A,Pišlar A,Frlan R,Kos J,Gobec S,Knez D,Abarbri M
Abstract : Structurally diverse heterotricyclic compounds are recognized as monoamine oxidase (MAO) inhibitors and thus represent an appealing scaffold in development and optimization of novel MAO inhibitors. Herein we explored the chemical space of pyrimido[1,2-b]indazoles as MAO inhibitors by preparing a small library of (hetero)aryl derivatives. An efficient synthetic strategy was developed starting from commercially available 1H-indazol-3-amines, which were converted to various 3-bromoheterotricyclic derivatives and further functionalized via Suzuki-Miyaura coupling reaction. Derivatives 4a-t selectively inhibited human MAO-B isoform in a reversible and competitive manner as confirmed by kinetic experiments and docking studies. Selected derivatives were not cytotoxic to neuroblastoma SH-SY5Y cells. Moreover, analogue 4i protected human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine-induced cell death, which confirms the applicability of the pyrimido[1,2-b]indazoles as potential antiparkinsonian agents.
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Inhibition of recombinant human MAOA using kynuramine as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by fluorescence assay
|
Homo sapiens
|
830.0
nM
|
|
Journal : Bioorg Med Chem
Title : Novel 3-benzylidene/benzylphthalide Mannich base derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.
Year : 2021
Volume : 35
First Page : 116074
Last Page : 116074
Authors : Cao Z,Song Q,Yu G,Liu Z,Cong S,Tan Z,Deng Y
Abstract : To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC = 9.18 × 10 and 6.16 × 10 μM, respectively), good MAO-B inhibitory activity (IC = 5.88 μM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu-induced Aβ aggregation inhibitory potency, disaggregation ability on Aβ fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.
|
Inhibition of recombinant human MAOB using kynuramine as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by fluorescence assay
|
Homo sapiens
|
23.0
nM
|
|
Journal : Bioorg Med Chem
Title : Novel 3-benzylidene/benzylphthalide Mannich base derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.
Year : 2021
Volume : 35
First Page : 116074
Last Page : 116074
Authors : Cao Z,Song Q,Yu G,Liu Z,Cong S,Tan Z,Deng Y
Abstract : To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC = 9.18 × 10 and 6.16 × 10 μM, respectively), good MAO-B inhibitory activity (IC = 5.88 μM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu-induced Aβ aggregation inhibitory potency, disaggregation ability on Aβ fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.
|
Inhibition of recombinant human MAOA expressed in baculovirus infected BTI insect cells at 100 uM using p-tyramine as substrate measured after 15 mins by Amplex red reagent based fluorescence assay relative to control
|
Homo sapiens
|
47.91
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of rasagiline-clorgyline hybrids as novel dual inhibitors of monoamine oxidase-B and amyloid-β aggregation against Alzheimer's disease.
Year : 2020
Volume : 202
First Page : 112475
Last Page : 112475
Authors : Xie SS,Liu J,Tang C,Pang C,Li Q,Qin Y,Nong X,Zhang Z,Guo J,Cheng M,Tang W,Liang N,Jiang N
Abstract : A series of rasagiline-clorgyline hybrids was designed, synthesized and investigated in vitro for their inhibition of monoamine oxidase and amyloid-β aggregation. Most of compounds were found to be selective and highly potent hMAO-B inhibitors showing IC values in the nanomolar, and exhibited a moderate inhibition of amyloid-β aggregation. 7-((5-(methyl(prop-2-yn-1-yl)amino) pentyl)oxy)chroman-4-one (6j) was the most interesting compound identified in this research, endowed with higher hMAO-B potency (IC = 4 nM) and selectivity (SI > 25000) compared to the reference selective inhibitor rasagiline (IC = 141 nM, SI > 355), and exhibited good inhibitory activity against Aβ aggregation (40.78%, 25 μM). Kinetic and molecular modeling studies revealed that 6j was a competitive reversible inhibitor for hMAO-B. Moreover, compound 6j displayed low toxicity and good neuroprotective effects in SH-SY5Y cell assay, and could penetrate the blood-brain barrier according to the parallel artificial membrane permeability assay. Pharmacokinetics assay revealed that compound 6j possessed good pharmacokinetic profiles after intravenous and oral administrations. Overall, these results highlighted that compound 6j was an effective and promising multitarget agent against Alzheimer's disease.
|
Inhibition of recombinant human MAOB expressed in baculovirus infected BTI insect cells using p-tyramine as substrate measured after 15 mins by Amplex red reagent based fluorescence assay
|
Homo sapiens
|
141.7
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of rasagiline-clorgyline hybrids as novel dual inhibitors of monoamine oxidase-B and amyloid-β aggregation against Alzheimer's disease.
Year : 2020
Volume : 202
First Page : 112475
Last Page : 112475
Authors : Xie SS,Liu J,Tang C,Pang C,Li Q,Qin Y,Nong X,Zhang Z,Guo J,Cheng M,Tang W,Liang N,Jiang N
Abstract : A series of rasagiline-clorgyline hybrids was designed, synthesized and investigated in vitro for their inhibition of monoamine oxidase and amyloid-β aggregation. Most of compounds were found to be selective and highly potent hMAO-B inhibitors showing IC values in the nanomolar, and exhibited a moderate inhibition of amyloid-β aggregation. 7-((5-(methyl(prop-2-yn-1-yl)amino) pentyl)oxy)chroman-4-one (6j) was the most interesting compound identified in this research, endowed with higher hMAO-B potency (IC = 4 nM) and selectivity (SI > 25000) compared to the reference selective inhibitor rasagiline (IC = 141 nM, SI > 355), and exhibited good inhibitory activity against Aβ aggregation (40.78%, 25 μM). Kinetic and molecular modeling studies revealed that 6j was a competitive reversible inhibitor for hMAO-B. Moreover, compound 6j displayed low toxicity and good neuroprotective effects in SH-SY5Y cell assay, and could penetrate the blood-brain barrier according to the parallel artificial membrane permeability assay. Pharmacokinetics assay revealed that compound 6j possessed good pharmacokinetic profiles after intravenous and oral administrations. Overall, these results highlighted that compound 6j was an effective and promising multitarget agent against Alzheimer's disease.
|
Inhibition of recombinant human MAO-B expressed in baculovirus infected BTI-TN- 5B1-4 insect cells using kynuramine as substrate preincubated for 10 mins in presence of substrate followed by enzyme addition and measured every minute for 30 mins by spectrophotometry analysis
|
Homo sapiens
|
45.7
nM
|
|
|
Inhibition of human MAO-B
|
Homo sapiens
|
6.0
nM
|
|
|
Inhibition of human recombinant MAO-B by multimode plate reader assay
|
Homo sapiens
|
28.1
nM
|
|
|
Inhibition of human recombinant MAO-A by multimode plate reader assay
|
Homo sapiens
|
587.0
nM
|
|
